Preserving and disinfecting



Patented June 20, 1950 UNITED STATES PATENT OFFICE PBESERVING AND DISINFECTING COMPOSITION Albert L. Bawlins, Grosse Pointe Woods, Mich; assignor to Parke, Davis & Company, Detroit, Mich, a corporation of Michigan No Drawing. Application September 21, 1946, Serial No. 698,426

filed September 4, 1942, now abandoned, and the invention relates to oils and oily compositions which are self-sterilizing and which are also useful for preserving and disinfecting materials with which they are brought into contact.

Most germicides exercise their disinfecting and preserving action in aqueous solution or in the presence of ahueous liquids. On the other hand, substantially dry oils or preparations consisting mainly of oils with little or no water present, are known to be extremely dimcult to sterilize and preserve in a sterile condition. Probably one reason for this state of aifairs is that the more powerful germicides are water-soluble but are not soluble in oils. Furthermore, the relatively few compounds of demonstrable disinfecting properties which are soluble in oils are so feebly germicidal in their action or of such low oil solubility, that they are unsatisfactory for the purpose of making self-sterilizing oil preparations.

It is therefore an object of the present invention to provide vegetable oil solutions containing a new type of oil soluble germicide capable of exercising a surprising germicidal activity in the 1 oil and even in the absence of any substantial amounts of water or aqueous fluids.

The invention is of great value in preparing medicaments and overcomes some very important practical problems which have always been present heretofore. For example, it is the common practice in the drug and pharmaceutical industries to package oily products for injection purposes in relatively large vials or packages containing enough material to provide for a considerable number of injections. Usually, the bottle, vial or other container for the oily preparation has a puncturable closure or rubber stopper or cover through which a hypodermic needle is inserted each time that enough material is withdrawn for a single injection. A very serious objection to these oily preparations is, that they are likely to become contaminated with infectious matter which can thus be transmitted by way of the container contents from one patient to the other.

It is a further object of this invention to provide oils and oily preparations which are sterile and which may themselves be directly employed by application to the surfaces of the body or by injection and which can, if desired, be put up in multiple dose packages or which can serve as carriers or as solvents for various medica- 5 ments.

A further object of the invention is the provision of oily germicides and fungicidal products which can be used on or in the human body without irritation and toxic manifestations. For example, it is an object to provide a vegetable oil composition which can be rubbed on the skin, as

for instance, on the hands and arms, of workmen in machine and tool industries where cutting machines operating with cutting oils of highly-infectious character are used. Another field of use is to impregnate the leather or other material of shoes that is in direct contact with the feet of the wearer, causing a continual release of highly active germicidal and fungicidal action, thereby preventing "athlete's foot" and infections of the feet resulting from breaks in the skin.

The above and other objects of the invention are attained by incorporating in a vegetable oil one or more members of a class of quaternary amnmonium compounds having the general form a,

Hr-OR water but in vegetable oils as well. The oil solu- I bility of these quaternary ammonium salts is unique in that it is very rapid and so great thatthese, compounds may be properly said to be miscible with vegetable oils, whereas the known quaternary ammonium salts only dissolve in so vegetable oils to the extent of a fraction of one per cent. Attempts have been made to increase the oil solubility oi these latter salts by adding solubilizers such as benzyl alcohol to the vegetable oils. However, these solubiliaers not only fail to appreciably increase the oil solubility of the known quaternary ammonium salts but also impart undesirable toxic and irritating effects to the oil solutions thus rendering them unsuitable for topical as well as parenteral use.

These new quaternary ammonium salts also dliler from the known quaternary ammonium salts in that they exercise a high order of germicidal activity even in the absence of substantial amounts of water. The germicdal properties of these compounds are surprising in view of the fact that they contain a benzyl group on the nitrogen atom which is known to have a deleterious effect on the germicidal activity and to increase the toxicity of high molecular weight quaternary ammonium salts. However, I have found that this particular class 01' high molecular weight quaternary ammonium salts having a benzyl group and two methyl groups attached to the nitrogen atom exhibits a higher degree of germicidal activity and about the same toxicity as the corresponding quaternary ammonium salts having three lower alkyl groups attached to the nitrogen atom.

The quaternary ammonium compounds used in the practice of the present invention can be 30 prepared by any of the known methods for converting a quaternary ammonium compound, such as thehydroxide, into salts with various acids. The method usually used is to react the quaternary ammonium salt of an acid forming an insoluble silver salt with moist silver oxide in aqueous solution to obtain the quaternary ammonium hydroxide and then to neutralize the latter compound with an alkoxyacetic acid.

The invention is illustrated by the following examples.

Example 1.p-t Octulphenozyethozyethyl dimethyl-benzul-ammonium n-octylozyacetate 011, CH: om-ocn -dOoomomo-cmcmr i Ha 6H:

product by heating it for a short time in vacuo.

The residue consists of the desired p-t-octylphenoxyethoxyethyl-dimethyl .benzyl ammonium n-octyloxyacetate. It is a thick viscous liquid having a slightly ambercolor and may be slightly opaque.

This product can be incorporated or dissolved in any suitable vegetable to obtain a self-sterilizing oil preparation. Only very small quantities of this compound, for example 0.5% or less are necessary to convert vegetable oils into rapidly self-sterilizing preparations. However. the high solubility of this compound in vegetable oils makes it possible to prepare more highly germicidal oil solutions if desired. These more concentrated solutions may either be used as such or diluted with a vegetable oil before use. Some of the more common vegetable oils in which this salt may be dissolved are olive, peanut, cottonseed and linseed oils. It may also be added to oil solutions containing various oil-soluble medicaments to render these preparations selfsterilizing.

This compound also possesses the unique property of being very soluble in water as well as in oil and when dissolved in water it also exhibits a high degree of germicidal activity.

Example 2.p-t Butylphenoxyethozuethyl dimethyl-benzyl-ammonium n-octyloxyacetate ver nitrate as described in Example 1, is added to a solution of 100 g. of p-t-butylphenoxyethoxyethyl-dimethyl-benzyl-ammonium bromide in 0H. CH:

I H10-C 31111 (1t) Moist silver oxide (prepared by dissolving g. of silver nitrate in 250 cc. of distilled water, adding 45 cc. 01' 40% sodium hydroxide solution and washing the precipitated oxide until .free from alkali) is added to 100 g. of p-t-octylphenoxyethoxyethyl-dimethyl benzyl ammonium chloride in 500 cc. of distilled water. The mixture is stirred for four hours, filtered and'the filtrate tested for halogen. It the test is negative the solution of the quaternaryammonium hydroxide is ready to use in the next step.

Octyloxyacetic acid is added to the solution of the quaternary ammonium hydroxide until the pH falls to between 7.7, .and 7.5, the solution stirred for a short time and then evaporated to dryness under reduced pressure. From time to time it is advantageous to add alcohol to prevent excessive foaming during the distillation. After all the water has been distilled the residual product is dried by adding an equal volume of absolute ethanol and distilling oil the ethanol under reduced pressure. This drying procedure may .be repeated several times and finally the last traces of water removed from the 250 cc. of distilled water. The mixture is stirred for three hours and the insoluble silver oxidesilver bromide mixture removed by filtration. Octyloxyacetic acid is added to the filtrate containing the quaternary ammonium hydroxide until the pH of the solution falls'to about 7.5. The solution is evaporated to dryness under reduced pressure and the water remaining in the product removed by adding benzene and distilling voif the benzene under reduced pressure. After this drying process has been repeated several times the last traces of benzene and water are removed by heating the residue for a short time under reduced pressure. The p-t-butylphenoxyethoxvethyl-dimethyl benzyl vammonium n-octyloxyacetate obtained in this manner is a thick, viscous, slightly amber colored liquid. It is readily soluble in veg table oils to give selfsterilizing preparations. Because of this oil solubility and germicidal activity it finds particular use in oil solutions containing medicaments wherein it serves both as a preservative and as a germicide to destroy any pathogenic organisms introduced into the solution during use.

a Example 3. p-t-Oetflphennyethmethyl-dimethIl-benzyl-ammoniam n-decillozyacetate added to a solution of 52 g. of silver nitrate dissolved in 150 cc. of distilled water. The silver A solution of p-t-octylphenoxyetboxyethyl-dimethyl-ammonium hydroxide, produced as described in Example 1 from 100 g. of the corresponding quaternary ammonium chloride, is

' quickly soluble in vegetable oils or solutions oi.

medicaments in vegetable oils to give stable. selfsterilizing oil solutions. In general, the amount of germicide necessary to accomplish this result is small and is of the order of about 0.5% or less.

Example 4. p-Methylphcnoxuethoxuethyl-dimethyl-benzyl-ammonium n-dodeculozvacetate CH; OH:

I cnroo-cmcmo-cmcnm 46 g. of silver nitrate is dissolved in 200 cc. of distilled water and 17.5 g. of sodium hydroxide in 50 cc. of water added. The precipitated silver oxide is collected and washed with distilled water until free from alkali.

The moist silver oxide prepared as described above is added to a solution 01' 100 g. of p-methylphenoxyethoxyethyl-dimethyl-benzyl-ammonium chloride in 500 cc. of distilled water and the resulting mixture stirred for four hours. The silver oxide-silver chloride mixture is removed by filtration and the filtrate containing the quaternary ammonium hydroxide compound treated with ndodecyloxyacetic acid until all the base has been neutralized. The solution (pH about 7) containing the desired quaternary ammonium n-dodecyloxyacetate is evaporated to dryness under reduced pressure. The last traces of water are removed from the residue by adding dry benzene and distilling oil. the benzene under reduced pressure. The product is a thick viscous liquid having a slight amber color.

The compound of this examplepossesses germicidal and physical properties similar to those of the compounds of the foregoing examples.

Example 5. n Decyl dimethyl-benzvl-ammonium n-Octyloxyacetate CH: CH:

oxide is collected, washed with distilled water until free from alkali and added to a solution of 100 g. of n-decyl-dimethyl-benzyl-ammonium chloride in 500 cc. of water. The mixture is stirred for four hours and filtered to obtain a solution of n-decyl-dimethyl-benzyl-ammonium hydroxide. Octyloxyacetlc acid is added to the filtrate in small portions until the pH falls to between 7.5 and 7.7 and the solution evaporated to dryness under reduced pressure. The product is dried by adding absolute ethanol and distilling oil. the ethanol in vacuo. lifter this drying process has been repeated several times the product is heated under reduced pressure for a short time to remove the last traces of water and ethanol. The product obtained in this manner is a thick, viscous, amber-colored liquid.

The compound or this example is soluble in water and in vegetable oils. Because of its high solubility in vegetable oils and high degree of germicidal activity, it finds particular use in the preparation of self-sterilizing vegetable oil solutions of medicaments.

65 g. of silver nitrate is dissolved in 300 cc. of

distilled water and a solution of 25 g. of sodium hydroxide in cc. oi! distilled water added. The precipitated silver oxide is collected and washed with distilled water until free from al- The moist silver oxide is added to a solution of 100 g. of n-hexadecyl-dimethyl-benzyl-ammonium chloride in 600 cc. of distilled water and the resulting mixture stirred for five hours. The silver oxide-silver chloride mixture is removed by filtration and the filtrate containing the quaternary ammonium hydroxide compound treated with n-octyloxyacetic acid until all the base has been neutralized. (The final pH of the solution should be about 7.5.) The solution is evaporated and the residue treated with an equal volume of absolute ethanol. The ethanol is distilled on under reduced pressureand the residue heated for a short time under reduced pressure to remove the last traces of moisture. The residue which is a light. amber liquid consists of the desired n-hexadecyl-dimethyl-benzyl-ammonium n-octyloxyacetate. v

The compound of this example is readily soluble in vegetable oils to produce a solution exhibiting germicidal properties. This preparation is notirritatingtotheskinandmaybeusedby garage mechanics and the like to remove grease 50 of 10 N sodium hydroxide solution is 15 from the and arms.

7 Example 7.-n-Octadecyl-dimethyl-beazylammonium nhendecylozuacetate OH: CH;

A solution of 21 g. of sodium hydroxide in 100 cc. ,of distilled water is added to a solution of 60 g. of silver nitrate in 300 cc. of distilled water and the resulting silver oxide collected by filtration. The oxide is washed with distilled water until free of alkali and then added toa solution of 100 g. of n-octadecyl-dimethyl-benzyl-ammonium chloride in 700 cc. of water. The resulting mixture is stirred for five hours and the silver chloride-silver oxide removed by filtration. n-Hendecyloxyacetic acid is added to the filtrate containing the quaternary ammonium hydroxide until the pH falls to between 7.5 and 7.7 and the neutralized solution evaporated to dryness under reduced pressure. The residue is treated with an equal volume of absolute ethanol and the alcohol distilled oif under reduced pressure. This drying process with alcohol is repeated several times and the last traces of moisture removed by heating the residue for a short time under reduced pressure. The residue which consists of the desired n-octadecyl-dimethyl-benzyl-ammonium nhendecyloxyacetate is a thick, viscous liquid which has a, slightly amber color.

This product can be added to rubber capped multiple dose packages of medicaments in vegetable oils to produce a preparation which is selfsterilizing, e. g. it does not become contaminated with pathogenic organisms even when an unsterilized hypodermic needle is used to withdraw a dose from the vial.

8 liquid consists of the desired n-tetradecvl-dimethyl-benzyl-ammonium n-nonyloxyacetate.

The compound of this example possesses germicidal and physical properties similar to those exhibited by the compounds of the previous examples. r

What I claim as my invention is:

1. A self-sterilizing vegetable oil solution containing as an active germicidal constituent thereof a quaternary ammonium compound of the formula,

where R is a. member of the class consisting of alkylphenoxyalkoxyalkyl radicals containing at least eleven carbon atoms and straight chain alkyl radicals containing ten to eighteen carbon atoms inclusive and R1 is a straight chain alkyl radical containing six to twelve carbon atoms inclusive.

2. A self-sterilizing vegetable oil solution containing as an active germicidal constituent thereof a quaternary ammonium compound of the formula,

'- CH: CH3

43 +=O om-o-n, where R is an alkylphenoxyalkoxyalkyl radical containing at least eleven carbon atoms and R1 is a straight chain alkyl radical containing six to twelve carbon atoms inclusive.

3. A self-sterilizing vegetable all solution containing as an active germicidal constituent thereof p-t-octylphenoxyethoxyethyl-dimethy1- benzyl-ammonium n-octyloxyacetate of the formula,

Example 8.n-Tetradecyl-dimethz/l-benzylammonium n-nonyloxyacetate //CH: CH;

g. of sodium hydroxide dissolved in 100 cc. of distilled water is added to a solution of 70 g. of silver nitrate in 300 cc. of distilled water and the silver oxide which precipitates collected and washed free from alkali. The moist silver oxide is then added to a solution of 100 g. of n-tetradecyl-dimethyl-benzyl-ammonium chloride in 703 cc. of water and the mixture stirred for five hours. The inorganic salts are removed by filtration and the filtrate containing the quaternary ammonium hydroxide compound treated with n-nonyloxyacetic acid until the pH is about 7.3 to 7.5. The neutralized solution is evaporated to dryness under reduced pressure and the residue dried by adding several portions of absolute ethanol and removing each portion by distillation in vacuo. The residue which is a viscous, yellow colored 4. A self-sterilizing vegetable oil solution containing as an active germicidal constituent thereof p-methylphenoxyethoxyethyl-dimethylbenzyl-ammonium n-dodecyloxyacetate of the formula,

CH; CH;

5. A self-sterilizing vegetable oil solution containing as an active germicidal constituent thereof a quaternary ammonium compound of the formula,

where R is a straight chain alkyl radical containing ten to eighteen carbon atoms inclusive and R1 is a straight chain alkyl radical containing six to twelve carbon atoms inclusive.

6. A self-sterilizing vegetable oil solution containing as an active germicidal constituent thereof n-tetradecyl-dimethyl-benzyl-ammonium 5 formula,

CH1 CH3 R l/ where R is a member of the class consisting of alyklphenoxyalkoxyalkyl radicals containing at least eleven carbon atoms and straight chain 25 alkyl radicals containing ten to eighteen carbon atoms inclusive and R1 is a straight chain alkyl radical containing six to twelve carbon atoms inclusive.

8. A quaternary ammonium compound of the so formula,

where R is an alkylphenoxyalkoxyalkyl radical containing at least eleven carbon atoms and R; is a straight chain alkyl radical containing six to twelve carbon atoms inclusive.

11. A quaternary ammonium compound of the formula,

where R is a straight chain alk'yl radical containing ten to eighteen carbon atoms inclusive and R1 is a straight chain alkyl radical containing six to twelve carbon atoms inclusive.

12. n-Tetradecyl dimethyl-benzyl-ammonium n-nonyloxyacetate having the formula,

13. p t Butylphenoxyethoxyethyl-dimethylbenzyl-ammonium n-octyloxyacetate having the formula,

OH; OH:

cm omi-O-o-omcmo-omom- 14. p t Octylphenoxyethoxyethyl-dimethylbenzyl-ammonium n-decyloxyacetate having the formula,

OH: OH!

9. p t Octylphenoxyethoxyethyl dimethylbenzyl-ammonium n-octyloxyacetate having the 15. A self-sterilizing vegetable oil solution containing as an active germicidal constituent formula, thereof p-t-butylphenoxyethoiwethyl-dimethylom OH: 015 cm amt-om-t-O-o-omomo-omcrm on, on, o on.-C

=0 tLHa-O-Oflc 10. p Methylphenoxyethoxvethyl dimethylbenzyl-ammonium n-dodecyloxyacetate having the formula,

onrO-o-cmommomomn (L\OEI-O JJHPO-OI I benzyl-ammonium n-octyloxyacetate of the formula,

11 12 18. A self-sterilizing vegetable oil solution con- 01' p-t-octylphenoxyethoxyethyl-dlmethyl-benzyltainlng as an active germicidal constituent thereammonium n-decyloxyacetate 01 the formula,

on; 0H: CH; 011.

HgO-OmHn ('n) ALBERT L. RAWLINS.

REFERENCES CITED The following references are of record in the file of this patent: I

UNITED STATES PATENTS Number Name Date 2,086,585 Taub July 13, 1937 2,087,132 Taub July 13, 1937 2,137,465 Thackston Nov. 22, 1938 2,176,896 Epstein Oct. 24, 1939 2,229,024 Bruson Jan. 21, 1941 2,295,504 Shelton Sept. 8, 1942 2,295,505 Shelton Sept. 8, 1942 2,380,877 Shelton July 31, 1945 

1. A SELF-STERILIZING VEGETABLE OIL SOLUTION CONTAINING AS AN ACTIVE GERMICIDAL CONSTITUENT THEREOF A QUATERNARY AMMONIUM COMPOUND OF THE FORMULA. 